Novel approaches for the treatment of cocaine addiction are urgently needed. ImmuLogic Pharmaceutical Corporation is developing a therapeutic for cocaine addiction based on vaccination of cocaine addicts with a cocaine-protein conjugate. This treatment induces an anti-cocaine antibody response that binds cocaine in the patient and reduces the entry of cocaine into the brain. As a result, the pharmacologic effect of the drug is reduced and it is anticipated that the patient will receive reduced gratification from the use of cocaine. With this as background, the specific aims of this project are: 1. To analyze the human antibody response induced by cocaine vaccine. This would involve analyzing the serum antibody response of the patients receiving the cocaine vaccine in the Phase I clinical trial to be conducted by Dr. Kosten (Projects 3a and 3b). Assays would be developed to evaluate the levels of antibody specific for the conjugate, for cocaine, and for the carrier protein in human serum. The cocaine binding capacity and the specificity of the antibody for metabolites and derivatives of cocaine would be assessed. Analysis of serum antibody responses would continue throughout the funding period to support the clinical trials described by Drs. Kosten (Projects 3a and 3b) and Fischman (Project 4). 2. To examine the feasibility of using mazindol and other new medications in association with the vaccine. This entails exploring the effects of these drugs on the immunogenicity of the cocaine vaccine and carrying out experiments in an effort to determine whether treatment with mazindol or other medications amplify the effects of antibodies against cocaine on the pharmacokinetics of the compound. 3. To evaluate the feasibility of a polyclonal passive antibody approach. Following transfer of high-titer immune murine Ig to naive mice, the resulting antibody levels would be monitored. Moreover, the effects of the transferred antibody would be measured on the pharmacokinetics of cocaine, with emphasis on the ability of the antibody to affect the distribution of repeated doses of cocaine. In addition, experiments would be carried out to determine whether passive transfer of antibody affects the ability to actively immunize with the cocaine vaccine. 4. To examine the oral immunogenicity of the vaccine. Oral immunization may increase the pool of anti-cocaine antibody available for binding cocaine. Therefore, efforts would be made to evaluate the oral immunogenicity of the vaccine, both alone and in association with intramuscular immunization. Moreover, the ability of cocaine-specific IgA to alter the pharmacokinetics of cocaine would be tested, with particular emphasis on repeated dosing with the drug. It is hoped that, together, the preceding experiments will evaluate the immogenicity of the cocaine vaccine in human subjects and lay the groundwork for future clinical approaches.